Virus-targeted therapeutic for EBV-Associated Malignancies

EBV 相关恶性肿瘤的病毒靶向治疗

• 批准号: 9312763
• 负责人: SUSAN Park PERRINE
• 金额: $ 51.96万
• 依托单位: PHOENICIA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312763
• 关键词: Acquired Immunodeficiency Syndrome; Adverse event; African Burkitt' s lymphoma; Animal Model; Antiviral Agents; B-Cell Lymphomas; Breast Carcinoma; Burkitt Lymphoma; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; Data; Databases; Development; Drug Exposure; EBV-associated malignancy; Enzymes; Family; Ganciclovir; Gene Expression; Goals; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Human Herpesvirus 8; Lead; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Malignant lymphoid neoplasm; Measurable; Nasopharynx Carcinoma; Neoplasms; Normal Cell; Oral; Outcome; Outpatients; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Play; Population; Prodrugs; Protein Kinase; Protocols documentation; Radiation; Radiation therapy; Refractory; Regimen; Research Personnel; Resistance; Role; Safety; Site; Small Business Innovation Research Grant; Stomach Carcinoma; System; TK Gene; Therapeutic; Thymidine Kinase; Toxicology; Transplantation; Treatment Protocols; Validation; Viral; Viral Drug Resistance; Viral Genome; Virus; antiviral nucleoside analog; chemotherapy; design; gammaherpesvirus; killings; meetings; member; neoplastic cell; nucleoside analog; oncology; outcome forecast; partial response; pre-clinical; preclinical development; prototype; public health relevance; research clinical testing; response; sarcoma; targeted treatment; therapeutic evaluation; tumor; virus development

 DESCRIPTION (provided by applicant) Epstein-Barr virus (EBV) is associated with a number of human malignancies, and likely plays a causal role in two endemic tumors: African Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC). Clonal EBV can be found in Burkitt's lymphomas, T/NK lymphomas, and post-transplant lymphoproliferative disorders (LPD), as well as some T- and B-cell lymphomas, and half of Hodgkin's lymphomas. In addition, EBV may be involved in the development of other neoplasias, including AIDS-related sarcomas, and gastric carcinomas, and certain breast carcinomas. However, we have demonstrated that merely the very presence of the virus in a tumor provides the opportunity for a targeted therapeutic strategy. EBV persists in these tumors in a dormant or "latent" state. Many Herpes-family virus-infected cells can be killed by nucleoside analog antiviral pro-drugs like ganciclovir, which targe the viral thymidine kinase (TK) enzyme. EBV is resistant to these antiviral agents because latently-infected tumor cells do not express the viral (TK) enzyme. We have demonstrated that selected agents which induce the EBV-TK gene expression in the tumor cells renders the tumor susceptible to standard anti-viral agents. This is a tumor-targeted therapy, in that only the tumor cells (containing EBV) are killed - normal cells are spared. We have conducted a successful Phase I/II study of this virus-targeted therapeutic approach in patients with EBV-associated lymphoid malignancies, all of which were resistant to conventional radiation and chemotherapy. Our targeted therapy produced complete clinical responses (CRs) in 26% of patients, and good partial responses (PRs) in an additional 40% within one treatment cycle (total tumor response rate of 67%). This is an exceptionally high rate of response, and the adverse event profile was favorable. The overall goal of this SBIR proposal is to develop a more potent, more selective, and more patient-accessible virus-targeted therapeutic for testing in EBV+ malignancies. In our Phase I period, we have screened, validated, and selected a highly-potent, clinical-stage lead inducing agent, which is orally-available and has significant human safety data, for use in combination with an anti-viral agent for EBV lymphomas. In this Phase II proposal, we will complete the preclinical development of the virus-inducing agent for this specific indication, generate data to expand its potential therapeutic application and value, and prepare for a Phase II proof-of-concept clinical trial. Our Specific Aims in this Phase II Proposal are: 1.) Optimize lead compound - Refine this EBV/KSHV-targeted therapeutic regimen in animal models; 2.) Expand application of this therapeutic approach into other herpesvirus-associated malignancies; 3.) Complete pre-clinical development; 4.) Clinical trial planning and set-up. Measurable Outcomes and Deliverables: i.) Optimization of treatment regimen; ii.) Validation of this virus-targeted approach in other malignancies associated with γ-herpesviruses; iii.) Complete pre-clinical development of lead compound; iv.) Filing of IND for phase II clinical trial.

 描述（由适用的）Epstein-Barr病毒（EBV）与许多人类恶性肿瘤有关，并且可能在两种内部肿瘤中起因果作用：非洲伯基特淋巴瘤（BL）和鼻咽癌（NPC）。克隆EBV可以在伯基特的淋巴瘤，T/NK淋巴瘤和移植后淋巴增生性疾病（LPD）以及一些T和B细胞淋巴瘤以及Hodgkin淋巴瘤的一半。此外，EBV可能参与了其他肿瘤的发展，包括与艾滋病相关的肉瘤，胃癌和某些乳腺癌。但是，我们已经证明，肿瘤中病毒的存在为有针对性的治疗策略提供了机会。 EBV在这些肿瘤中一直处于休眠状态或“潜在”状态。许多疱疹家族感染的细胞可以被核苷抗病毒促毒物（如Ganciclovir）杀死，该细胞靶向病毒性胸苷激酶（TK）酶。 EBV对这些抗病毒剂具有抗性，因为潜在感染的肿瘤细胞不表达病毒（TK）酶。我们已经证明，诱导肿瘤细胞中EBV-TK基因表达的精选药物使肿瘤容易受到标准抗病毒药的影响。这是一种靶向肿瘤的疗法，只有肿瘤 细胞（包含EBV）被杀死 - 普通细胞被保留。我们已经对与EBV相关的淋巴性恶性肿瘤患者进行了对这种病毒治疗方法的成功I/II期研究，所有这些方法都对常规放射和化学疗法有抵抗力。我们的靶向治疗在26％的患者中产生了完整的临床反应（CRS），并且在一个治疗周期内额外40％（总肿瘤反应率为67％），良好的部分反应（PR）。这是一个异常高的响应率，不良事件曲线是有利的。该SBIR提案的总体目标是发展具有EBV+恶性肿瘤测试的更具潜力，更具选择性且更容易获得的病毒靶向疗法。在我们的第一阶段时期，我们已经筛选，验证并选择了一种高度功能，临床阶段铅诱导的剂，该剂是口服可用并且具有重要的人体安全数据，可与EBV淋巴瘤的抗病毒剂结合使用。在此II阶段提案中，我们将完成该特定指征的病毒诱导药物的临床前开发，生成数据以扩大其潜在的治疗应用和价值，并为II期概念证明临床试验做准备。我们在此II阶段提案中的具体目的是：1。）优化铅化合物 - 在动物模型中完善该EBV/KSHV靶向的治疗方案； 2.）将这种治疗方法的应用扩展到其他与疱疹病毒相关的恶性肿瘤中； 3.）完整的临床前发展； 4.）临床试验计划和设置。可测量的结果和可交付成果：i。）优化治疗方案； ii。）在与γ-疱疹病毒相关的其他恶性肿瘤中验证这种靶向病毒的方法； iii。）铅化合物的完整临床前开发； iv。）为II期临床试验提交IND。